tbuckley/cabot-search huggingface dataset:
P39 Methotrexate induces epidermal DNA damage response and filaggrin in atopic eczema
Authors: Amaani B Hussain, Martina Elias, Simon Cockell, John Casement, Graham Smith, Yuchun Ding, Esme Nichols, Nick J Reynolds
Journal: British Journal of Dermatology (2023)

Abstract Methotrexate (MTX) is an effective treatment for atopic eczema (AE), but its mechanism of action remains undefined. Our previous work identified keratinocytes as a direct target of MTX by increasing epidermal differentiation. Evidence supports the concept of DNA damage-induced keratinocyte differentiation; however, this has not been characterized in the context of MTX. We tested the hypothesis that MTX may act therapeutically in AE by inducing DNA damage and activating downstream DNA damage response signalling pathways. Patients with AE starting MTX (initial dose 10 mg weekly) were recruited (n = 12). The FLG status was determined by DNA genotyping. Clinical data and skin biopsies from lesional and nonlesional skin were collected at week 0 (baseline), week 2 [visit 1 (V1)] and week 12 [visit 2 (V2)] following MTX initiation. γH2A.X, a marker of DNA damage, was quantified to explore the relationship between DNA damage secondary to MTX treatment and FLG status. γH2A.X and filaggrin protein epidermal immunostaining were quantified. The male-to-female ratio was 8 : 4 and median participant age was 45 years. Median Eczema Area and Severity Index (EASI) score improved from 23.5 (baseline, n = 12) to 14.6 at V1 (n = 12) and 9.0 at V2 (n = 8). Median Dermatology Life Quality Index reduced from 15 (baseline, n = 12) to 10.5 (V2, n = 8). Four patients were FLG heterozygotes and eight were FLG wild type. In combined analysis of all patients, epidermal γH2A.X increased in lesional skin at both time points [n = 6 (V1: P = 0.022; V2: P = 0.009)] and in nonlesional skin by V2 (n = 6; P = 0.021). γH2A.X increased in lesional skin at V2 in both FLG heterozygotes (P = 0.044) and wild types (P = 0.038). Epidermal filaggrin in lesional and nonlesional skin increased at V1 and V2 in all patients combined (n = 5; P = 0.029). Filaggrin increased in the nonlesional skin of FLG heterozygotes (P = 0.044) and in the lesional skin of FLG wild-type patients (P = 0.009) by V2. Transcriptomic (RNAseq) analysis was performed on skin biopsies (n = 11 patients; n = 42 samples). We explored the relationship of gene expression with severity (EASI) and FLG status. AKR1B10, IL22 and LGALS7 expression increased with disease severity. The AKR1B10 (regulates keratinocyte differentiation) and LGALS7 expression (expressed during barrier dysfunction) response with EASI was enhanced in FLG heterozygotes vs. wild-type patients. Canonical pathways were upregulated in lesional skin at V2 vs. baseline. Through epidermal immunostaining and transcriptomic gene analysis, we demonstrated evidence of DNA damage and filaggrin induction in patients with AE following MTX therapy, with associated improved disease outcomes.
PA10 You and Your Skin: developing and trialling a new history-taking aid for psychological wellbeing in children and young people with skin conditions
Authors: Rukshana Ali, Cheryl Choong, Jane Ravenscroft, Tess McPherson, Susannah Baron
Journal: British Journal of Dermatology (2023)

Abstract The mental health burden in children and young people (CYP) living with skin conditions is profound and well documented. There is a lack of integrated psychology/psychiatry provision within paediatric dermatology departments, and dermatologists can struggle to explore psychological wellbeing as part of their clinic consultations due to limited time and/or a lack of confidence and/or training. The British Society for Paediatric and Adolescent Dermatology formed a working group to address the mental health needs of CYP presenting with skin conditions. A multidisciplinary consensus group was formed to assess evidence and develop appropriate guidance. A systematic review found that no single psychological measure or patient-related outcome measure (PROM) adequately captures the psychological burden and impact of living with a skin condition. Patient feedback was clear that PROMs can be less useful than an appropriate clinical consultation. This identified a need for an appropriate clinical tool to help explore CYP psychological wellbeing as part of dermatology consultations: You and Your Skin (YAYS) was developed as a self-completed history-taking aid for CYP &amp;gt; 8 years old and a parent/carer for those &amp;lt; 8 years old. The YAYS was created iteratively using adapted validated and clinically relevant domains from the Children’s Dermatology Quality of Life Questionnaire, the Teenage Quality of Life Questionnaire, the British Association of Dermatologists Acne 3 questions and the Patient Health Questionnaire-9, including self-harm and risk. Questions explore how CYP feel about their skin today and how their skin condition has affected their daily life, caused embarrassment and bullying, and impacted on sleep and mood, and whether they had any thoughts of life not being worth living. The YAYS was co-developed with patients, parents/carers and an external expert stakeholder consensus group (dermatologists, psychologists, psychiatrists, general practitioners, nurse specialists and patient support groups) with revisions done according to feedback on the usability, accessibility and appropriateness of questions. This process has involved 12 revisions of YAYS for CYP and eight revisions of the YAYS parent/carer form, and has been trialled in three paediatric dermatology centres in London, Oxford and Nottingham with 354 CYP and 29 parent/carer forms completed to date. The YAYS development process, findings from YAYS and feedback will be presented. The purpose of YAYS is to enable CYP to raise issues and guide clinicians in evaluation and discussion of mental health concerns in CYP, collaboratively as part of their clinic appointment. Feedback has been very positive from CYP who feel empowered that the impact of their skin disease on all areas of wellbeing can be addressed.
DS16 Clinicopathological features of metastatic squamous cell carcinoma treated with Mohs micrographic surgery: a case series
Authors: Nicholas Stefanovic, Niall Cosgrave, Lisa Killion, Patrick Ormond, Benvon Moran, Alan Irvine, Rupert Barry
Journal: British Journal of Dermatology (2023)

Abstract Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte tumour with inherent metastatic potential. Approximately 4% of cSCCs metastasize locoregionally and/or distally. Mohs micrographic surgery (MMS) is efficacious, with cure rates in selected cases of 95–99%. Diagnoses of cSCC treated at St James’s Hospital between the years 2010 and 2019 were identified via histopathology reports. Clinicopathological and treatment data in cases with metastatic disease were collected. Nodal metastasis was defined as biopsy-confirmed cSCC in locoregional lymph nodes and/or supporting radiological evidence. During the timeframe, 3455 cSCCs occurred in 2522 patients. Metastatic disease was identified in 116 patients, with complete data available in 105 cases. Six patients had undergone MMS to the primary tumour. Mean age at time of surgery was 75.6 years (range 65–85); five patients were male. Tumours were located on the cheek (n = 2), ear (n = 2), lower eyelid and nasal tip. Mean time to first metastasis was 6.67 months (range 2–16). Two patients were immunosuppressed at time of metastasis. All patients demonstrated high-risk cSCC features, with four patients demonstrating very-high-risk features as defined by the British Association of Dermatologists. One patient received adjuvant radiotherapy prior to detectable metastasis. All patients were discussed at either skin or head and neck multidisciplinary team (MDT) meetings. No patient received preoperative imaging. This series highlights the importance of risk stratification in cSCC management, irrespective of treatment modality. Consideration should be given to patient age and relative immune status, with dedicated locoregional imaging being guided by MDT discussion.
P23 Primary penile melanoma and penile lichen sclerosus
Authors: Kate Dear, George Kravvas, Sharmaine Sim, Mariel James, Richard Watchorn, Aiman Haider, Peter Ellery, Alex Freeman, Hussain Alnajjar, Asif Muneer, Chris Bunker
Journal: British Journal of Dermatology (2023)

Abstract The association between squamous cell malignancies and genital lichen sclerosus (GLSc) is well established. There is an increasing literature regarding the relationship of GLSc with genital malignant melanoma (MM). While there have been several reported cases of vulvar melanoma associated with lichen sclerosus (LSc), there have been fewer cases published with regard to male genital (M)GLSc and penile (Pe)MM. The aims of this study were to explore the relationship between PeMM and MGLSc by reviewing all cases managed by our multidisciplinary service over a period of 11 years. All patients known to our tertiary urology and male genital dermatology service with a diagnosis of penile MM and where histology was available for review were identified over an 11-year period (2011–2022). Two independent dermatologists reviewed the clinical records and photographs where available. Two independent mutually blinded histopathologists reviewed the histology and recorded features of GLSc where present. In cases of discordance between histopathologists, a third independent histopathologist reviewed the cases. Eleven patients were identified for inclusion in the study. Overall, GLSc was present on histopathology in nine of 11 cases (82%). Findings were concordantly positive in five cases and concordantly negative in one case. In cases with discordant findings (n = 5), the third histopathologist determined GLSc to be present in four cases and absent in one case. Clinical photographs were available for three cases and clinical features of GLSc were seen in all of them; they also all had positive histopathological findings. Clinical notes, including electronic notes and letters, were available for review in eight cases. Symptoms in keeping with GLSc were mentioned in only one case, and signs suggestive of GLSc were documented in three cases. Penile MM is a rare entity accounting for 0.7% of penile cancer and 0.1% of MM cases. Like other malignancies, MM is a multifactorial disease caused by a combination of environmental factors and altered host responses contributing to an alteration of regulatory processes. Although ultraviolet exposure is important in the pathogenesis of extragenital MM, this cannot be a factor for genital disease. However, specific risk factors for genital MM have not yet been elucidated. To our knowledge, there have only been three previously documented cases (all from our group) of PeMM coexisting with GLSc. This present study finding of GLSc in 9 of 11 men with PeMM, is suggestive of a causative relationship. We postulate that this is related to chronic melanocytic distress created by chronic inflammation secondary to LSc.
BG04 Oleogel-S10 (birch triterpenes) in the treatment of epidermolysis bullosa wounds: 24-month efficacy and safety data from the EASE study
Authors: Dedee Murrell, Anna L. Bruckner, Eli Sprecher, Dimitra Kiritsi, Laura Maher, Tracy Cunningham, Johannes S. Kern
Journal: British Journal of Dermatology (2023)

Abstract Epidermolysis bullosa (EB) is a rare debilitating disorder characterized by skin fragility, blister formation and impaired wound healing. The abnormal wound healing seen in EB is a key driver for systemic disease and can lead to serious clinical complications, deformities and symptoms with a devastating impact on quality of life (QoL). The 90-day double-blind phase (DBP) of the phase III EASE study previously demonstrated accelerated wound healing for oleogel-S10 (birch triterpenes) vs. control gel in EB. Here, we report the safety and total wound burden results from the 24-month open-label phase (OLP), in which all patients received treatment with oleogel-S10. EB Disease Activity and Scarring Index (EBDASI) and body surface area percentage (BSAP) data are reported without visit windows to reflect a real-world situation more accurately, particularly considering the COVID-19 pandemic. The patient population was made up of those with dystrophic EB (n = 178; 86.8%) and junctional EB (n = 25; 12.2%). Further baseline characteristics are available in Table 1. In total, 141 patients (68.8%) completed the OLP. The mean (SD) treatment duration for all patients was 584.7 (246.1) days. Adverse events were reported in 77.1% of all patients in the OLP vs. 81.7% of those receiving oleogel-S10 in the DBP. Mean BSAP for patients treated with oleogel-S10 in the DBP reduced from 12.1% at study entry to 6.1% on completion of the EASE study. Similarly, the mean EBDASI skin activity score in the oleogel-S10 group improved from 19.6 to 15.1 at the end of the OLP. In addition, reductions in both BSAP and EBDASI from OLP baseline were observed in patients who transitioned from control gel to oleogel-S10 in the OLP. Oleogel-S10 has a reassuring long-term safety profile. Furthermore, the long-term impact of accelerated wound healing is evident through the sustained reduction in wound burden over time. This is encouraging given the regular reoccurrence of patients’ fragile wounds in the natural course of this chronic disease. Table 1Baseline characteristics
P08 Successful treatment of paediatric morphoea with tofacitinib
Authors: Junchi Tang, Wenyue Zheng, Bin Yang
Journal: British Journal of Dermatology (2023)

Abstract Morphoea is a chronic autoimmune fibrosing condition causing inflammation, skin sclerosis and underlying soft tissue. The Janus kinase (JAK)-STAT pathway is considered to be the downstream mediator in the process of promoting fibrosis by transforming growth factor-β, interleukin-6 and other factors and plays a signal transduction role in the process of fibrosis. JAK inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in systemic sclerosis (Celada LJ, Kropski JA, Herazo-Maya JD et al. PD-1 up-regulation on CD4(+) T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-beta1 production. Sci Transl Med 2018; 10). Here, we report the successful use of tofacitinib in two paediatric patients. Case 1 was a 6-year-old girl with a 4-year history of morphoea; case 2 was a 13-year-old boy, also with a 4-year history of morphoea. In case 1, we initiated tofacitinib therapy 2.5 mg twice daily, reduced the dose after 2 months and stopped using it after 8 months. For case 2, the dose was 5 mg twice daily for 5 months, considering the patient’s height and weight. We have seen a significant improvement in the appearance and pathology of the lesions. The Localized Scleroderma Cutaneous Assessment Tool (LoSCAT) was used to assess the disease activity and damage, and the post-treatment scores for both cases were significantly lower than before treatment. Skin biopsy in both cases after tofacitinib therapy revealed that collagen bundles were decreased in size and number, with decreased lymphocytic infiltration in the peripheral tissue. Immunofluorescence staining for case 1 showed that activated α-smooth muscle actin and myofibroblasts were significantly decreased after treatment of tofacitinib, mostly in the dermal papillary layer. The two patients remain under follow-up; neither of them has so far relapsed. To our knowledge, these are the first two paediatric cases of morphoea treated with tofacitinib to be reported in the literature. Disease progression was found to have been inhibited clinically and pathologically. The traditional treatment of morphoea with methotrexate, cyclophosphamide or mycophenolate mofetil is not invariably effective in our experience, especially in antifibrosis (Zhao M, Wu J, Wu H et al. Clinical treatment options in scleroderma: recommendations and comprehensive review. Clin Rev Allergy Immunol 2022; 62:273–91). Our results provide the rationale for large prospective cohort studies of tofacitinib in morphoea and other fibrotic disorders.
BT20 Straight to biopsy vs. face-to-face consultation for skin lesions referred on a 2-week wait pathway: a review of outcomes
Authors: Luke Brindley, Manrup Hunjan, Koharu Walker, Kelly Higgins, Paul Gazzani
Journal: British Journal of Dermatology (2023)

Abstract Teledermatology has become an essential tool in the triage and management of skin cancer referral pathways. The implementation of the process varies between dermatology departments. At a large multihospital trust, a retrospective service evaluation was conducted looking at the outcomes between two dermatology sites within the trust. Both use the same teledermatology platform to review all referrals made via a 2-week wait suspected cancer pathway for skin lesions. The main comparator was that one of the sites employs a straight to biopsy (STB) outcome as a potential pathway for referred lesions. The other site conducts face-to-face (F2F) review of suspicious lesions warranting biopsy first. Data were collected for all referrals made to both sites over a week in July 2021. A total of 506 lesions were referred across the two sites. Following teledermatology review at the site where STB was adopted, 32.2% (n = 96/298) of patients had a STB outcome and 33.9% (n = 101/298) had a F2F outcome. In comparison, 48.6% (n = 101/208) had a F2F outcome at the other site. Where STB was employed, biopsies were carried out for 13 intermediate lesions (actinic keratosis, superficial basal cell carcinoma, Bowen disease) vs. seven following F2F review at the other site. Rates of definitive surgery, for example wide local excision, were comparable between sites: 13.4% (STB) vs. 15.5%. Curettage and cautery was performed exclusively for lesions reviewed at the STB site, whereas at the other site, intermediate lesions were seen F2F and likely discharged following management with cryotherapy, topical treatments or conservative measures. The STB model can be appealing as it eliminates the need for a F2F review for lesions that require histological confirmation for diagnosis and management, saving valuable time and resources. However, the multiple stages involved in processing biopsies are costly and resource intensive when considering that many intermediate lesions can be treated from a clinical diagnosis alone. Biopsies are associated with increased morbidity and risk, unnecessary extra steps in patient care. With the Montgomery ruling, the process of consent must be robust and consider the individual values of each patient. Biopsies in more complex anatomical sites may pose additional difficulty when obtaining valid consent. The STB can have a role in the management of skin lesions and can streamline patient pathways. However, it does not replace good clinical acumen and, to remain cost-effective, needs to be employed in an appropriate manner.
PD14 Audit of urgent phototherapy referrals
Authors: Apeksha Shyamalie Dissanayake Perera, Amirtha Rajasekaran
Journal: British Journal of Dermatology (2023)

Abstract The British Association of Dermatologists’ (BAD) phototherapy guidelines state that patients referred urgently for phototherapy should start treatment within 3 weeks of referral and that if the patient is considered to require treatment urgently, then it should be started as soon as possible, to reduce patient discomfort and avoid the need for hospital admission. The prepandemic waiting time for urgent referrals, according to an audit in March 2021, was 6 weeks, but this time was even longer postpandemic. During the COVID-19 pandemic lockdown, the phototherapy service was suspended and then resumed in reduced capacity in our unit. The pandemic is also likely to have affected disease severity and patient’s concerns about treatment with systemic options. Our audit objective was to identify the time taken between referral to treatment start time for urgent referrals. Secondary objectives were to identify whether there was any prevalence of certain disease categories in deciding upon urgent referrals, and to identify if severity assessment scores were checked prior to urgent referrals by referring clinicians as per local guidelines. The audit was conducted retrospectively by including all urgent phototherapy referrals for 6 months between January and June 2022. Sixty-four urgent referral forms were analysed. The time taken between referral to treatment start time was 12 months. The majority of the urgent referrals (73%) were for eczema, 16% for psoriasis and 5% for mycosis fungoides. Other conditions such as polymorphic light eruptions, lichen planus and macular amyloidosis totalled 6% of referrals. Only 26% of referrals had documented disease severity scores. Thirty per cent of the referrals were &amp;lt; 18 years of age; young adults (19–25 years) accounted for 19% of referrals. Time taken between referral to treatment start time was 12 months, which significantly exceeded BAD standards. A number of factors affected this, including the impact of the COVID-19 lockdown on services and treatment capacity, patient choices and escalation of disease severity in lockdown, increased referrals with severe skin disease, preference in certain age groups such as children, and psychosocial factors. Patients with severe skin disease needing urgent treatment should be carefully triaged to receive treatment urgently, to avoid admission. Clinicians should assess this appropriately on a case-by-case basis and document disease severity scores and impact of skin disease in all urgent referrals.